1. Field of the Invention
The present invention relates to methods and compositions for the topical treatment of neuropathy. More particularly, the present invention relates to topical compositions including a combination of ingredients that provides a surprising degree of effective relief from the symptoms of neuropathy with minimal side effects and to methods for administering topical compositions to treat neuropathy. Preferred embodiments contemplate chemical, biological or physical means of reducing such side effects.
2. Description of the Related Art
Peripheral neuropathy is a condition involving nerve-end damage anywhere in the body. Peripheral neuropathy generally refers to a disorder that affects the peripheral nerves, most often manifested as one or a combination of motor, sensory, sensorimotor, or autonomic neural dysfunction. The wide variety of morphologies exhibited by peripheral neuropathies can each be uniquely attributed to an equally wide variety of causes. For instance, peripheral neuropathies can be genetically acquired, can result from a systemic disease, can manifest as a post-surgical complication, or can be induced by a toxic agent. Some toxic agents that cause neurotoxicities are therapeutic drugs, antineoplastic agents, contaminants in foods or medicinals, and environmental and industrial pollutants. As much as 3% of the population is estimated to be affected, if not greater.
Although a number of neuropathies are related to the disease diabetes mellitus, others, although not known to be related to diabetes are similar in their physiological effects on the peripheral vascular system. Such diseases include Raynaud's Phenomenon, including CREST syndrome, autoimmune diseases such as erythromatosis, and rheumatoid diseases. Other peripheral neuropathies include the following: HIV-associated neuropathy; nutritional deficiency-associated neuropathy; cranial nerve palsies; drug-induced neuropathy; industrial neuropathy; lymphomatous neuropathy; myelomatous neuropathy; multi-focal motor neuropathy; immune-mediated disorders, chronic idiopathic sensory neuropathy; carcinomatous neuropathy; acute pain autonomic neuropathy; alcoholic neuropathy; compressive neuropathy; vasculitic/ischaemic neuropathy; mono- and polyneuropathies.
For example, among the most important toxic agents causing peripheral neuropathy are therapeutic agents, particularly those used for the treatment of neoplastic disease. In certain cases, peripheral neuropathy is a major complication of cancer treatment and is the main factor limiting the dosage of chemotherapeutic agents that can be administered to a patient (Macdonald, Neurologic Clinics 9:955-967 (1991)). This is true for the commonly administered agents cisplatin, paclitaxel and vincristine (Broun, et al., Am. J. Clin. Oncol. 16:18-21 (1993); Macdonald, Neurologic Clinics 9:955-967 (1991); Casey, et al., Brain 96:69-86 (1973)). The identification of methods for preventing or alleviating dose-limiting peripheral neuropathologic side effects would allow higher, and more therapeutically effective doses of these chemotherapeutics to be administered to patients, i.e., the therapeutic efficacy of such chemotherapeutics is typically a function of dose and therefore, increasing dosage provides increased patient survival (Macdonald, Neurologic Clinics 9:955-967 (1991); Oxols, Seminars in Oncology 16, suppl. 6:22-30 (1989))
The N-methyl-D-aspartate (NMDA) receptor seems to play a major role in neuropathic pain and in the development of opioid tolerance. Experiments in both animals and humans have established that NMDA antagonists such as ketamine and dextromethorphan can alleviate neuropathic pain and reverse opioid tolerance. Unfortunately, only a few NMDA antagonists are clinically available and their use is limited by unacceptable side effects.
Generally, depressed NMDA receptor function is associated with an array of negative symptoms. They sometimes induce “psychotomimetic” side effects, symptoms resembling psychosis. Such side effects caused by NMDA receptor inhibitors can include hallucinations, paranoid delusions, confusion, difficulty concentrating, agitation, convulsions, alterations in mood, nightmares (Muir, K W; Lees K R (1995), and may exhibit personality changes and disorganized thinking. “Clinical experience with excitatory amino acid antagonist drugs”. Stroke 26 (3): 503-513.) catatonia (Aarts, M M; Tymianski M (2003). “Novel treatment of excitotoxicity: targeted disruption of intracellular signalling from glutamate receptors”. Biochemical Pharmacology 66 (6): 877-886.) ataxia (Kim A H, Kerchner G A, and Choi D W. (2002). “Blocking Excitotoxicity”. In CNS Neuroproteciton. Marcoux F W and Choi D W, editors. Springer, New York. Pages 3-36), anaesthesia (Kristensen, J D; Svensson B, and Gordh T Jr (1992). “The NMDA-receptor antagonist CPP abolishes neurogenic ‘wind-up pain’ after intrathecal administration in humans”. Pain 51 (2): 249-253. PMID 1484720.) and learning and memory deficits (Rockstroh, S; Emre M, Tarral A, and Pokorny R (1996). “Effects of the novel NMDA-receptor antagonist SDZ EAA 494 on memory and attention in humans”. Psychopharmacology 124 (3): 261-266.) In certain animals, such as rats, certain NMDA antagonists cause neurotoxicity and permanent brain injury (see, e.g., Olney J, Labruyerre J and Price M T. 1989. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science, Volume 244, Issue 4910, Pages 1360-1362; Ellison G. 1995. The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias. Brain Research. Brain Research Reviews, Volume 20, Issue 2, Pages 250-267).
The use of ketamine transdermally in an organogel has shown some promise in the treatment of neuropathy. Because ketamine is an N-methyl-D-aspartate receptor antagonist it blocks a cascade of intracellular events that inhibit the hyper excitability of spinal cord neurons. Animal data show that certain spontaneous pains and allodynia have been treated successfully with Ketamine. Also, in humans, phantom limb pain has been treated with some success (Nadine & Bouhassira, Acta. Neurol. Scand 1999 (Supp 173):12-24). Ketamine has been used experimentally to treat neuropathic pain by a variety of routes including the intravenous and subcutaneous. A topical form of low doses of Ketamine has shown some efficacy in treating painful neuropathy when other traditional medicines have failed. (Crowley et al., International Journal of Pharmaceutical Compounding 1998; 2:122-1273).
Other compositions have been employed, including combinations of individual compounds. U.S. Pat. No. 6,387,957 (Frome) relates to the treatment of Sympathetically Mediated Pain (SMP), which include various neuropathies, employing the compounds ketamine (NMDA receptor antagonist), amitriptyline (antidepressant), and guanethidine (sympathetic blocking agent), in combination or independently. U.S. Patent Publication Nos. 2004/0204366 and 2004/0101582 attack the problem with a spectrum of analgesic compounds including combinations of ketamine, gabapentin and clonodine. Other solutions have attempted to increase the absorption of the compounds, see, e.g., US Patent Publication. No. 2004/0076648. Each of these references is incorporated herein by reference.
PCT Publication WO 9807447 describes combinations of anti-epileptic compounds, including gabapentin, with NMDA receptor antagonists. PCT Publications WO 9912537 and WO 0053225 describe combinations of NMDA antagonists and GABA analogs, including gabapentin and pregabalin. PC Publication WO 0200434 describes the use of NMDA antagonists in the treatment of central neuropathic pain. PCT Publication WO 05102390 describes alpha-2-delta ligands in combination with NMDA antagonists as analgesics.
PCT Publication WO 03061656 describes a composition for treating disorders of the central nervous system comprising a GABA analog, such as gabapentin or pregabalin, with an NMDA receptor antagonist such as dextromethomorphan or d-methadone, optionally in combination with another pharmaceutically active substance.
PC Publications WO 9912537 and WO 0053225 describe combinations of anti-epileptic compounds, including gabapentin and pregabalin, in combination with NMDA antagonists as analgesics.
PC Publication WO 03091241 describes NR2B antagonists for a number of indications, together with alpha-2-delta ligands, e.g. gabapentin and pregabalin.
Accordingly, there remains a need in the art for effective treatments for neuropathies, and other neuropathic pains.